Sparsentan

来源：药渡 撰文：西江鱼     编辑：维他命 昨日（11月26日），诺华公司宣布其新药「阿曲生坦」（atrasentan）在国内提交上市申请，用于治疗原发性免疫球蛋白A肾病（IgAN）。 阿曲生坦作为一种在研口服内皮素A受体（ERA）拮抗剂，于近期被中国国家药监局药品审评中心（CDE）纳入优先审评通道，旨在快速降低有疾病进展风险的IgAN成人患者的蛋白尿水平。此前，阿曲生坦在美国的上市申请也已于2024年第二季度获得FDA受理，标志着其在全球范围内治疗IgAN领域取得重要进展。 来源：CDE官网 01 阿曲生坦的研发历程 阿曲生坦的研发历程充满挑战与突破，其研究始于对IgAN疾病机制的深入理解。IgAN是一种常见的慢性肾脏疾病，全球患病率约为2%-3%，主要表现为肾小球内沉积的免疫球蛋白A导致的慢性肾功能损害。该疾病发展缓慢而隐蔽，许多患者在确诊时已进入肾功能衰竭阶段，严重影响生活质量并使医疗费用骤增。因此，开发能有效降低蛋白尿、延缓肾功能恶化的药物显得尤为重要。 诺华公司在这一领域投入了大量资源，阿曲生坦便是其研究成果之一。早在2010年，阿曲生坦就已进入临床试验阶段，当时它被用于ASCEND研究，这是一项针对合并肾病的2型糖尿病患者的多中心随机双盲安慰剂对照研究。尽管该研究因体液潴留及心血管事件增加而提前终止，但阿曲生坦在减少蛋白尿方面的潜力已初步显现。 此后，阿曲生坦的研发并未停止，反而更加深入。随着对IgA肾病（IgAN）发病机制的深入研究，阿曲生坦作为内皮素A受体（ETA）拮抗剂的特性更加被重视。2022年，在欧洲肾脏病学会年会（ERA）上，阿曲生坦治疗IgAN的II期临床试验（AFFINITY研究）中期结果公布，显示其在降低蛋白尿方面具有显著疗效，且安全性良好。这一发现为阿曲生坦的进一步研发提供了有力支持。 随后，阿曲生坦的III期临床试验（ALIGN研究）在全球范围内展开，旨在评估其对高进展风险IgAN患者的疗效及安全性。2023年，ALIGN研究的中期分析结果揭晓，显示阿曲生坦在36周时可使IgAN患者的蛋白尿减少36.1%，且安全性良好。这些积极的研究结果为阿曲生坦的上市奠定了坚实基础。 02 阿曲生坦作用机制和优势 阿曲生坦的作用机制主要基于其对内皮素A受体（ETA）的拮抗作用。ETA受体的激活与蛋白尿升高、肾脏损伤、纤维化和肾功能丧失密切相关。阿曲生坦通过抑制ETA受体，减少蛋白尿的产生，从而延缓IgAN的疾病进展。 目前市场上已有一些用于治疗IgAN的药物，但它们在作用机制和疗效上各有特点。例如，司帕生坦是另一种ETA受体拮抗剂，但其同时抑制ETA和AT-1双靶点，需要停用抑制RAS药物，这使得其在临床应用中受到一定限制。此外，布地奈德迟释胶囊等糖皮质激素类药物也常用于IgAN的治疗，但长期使用可能带来一系列副作用，如骨质疏松、血糖升高等。 相比之下，阿曲生坦具有独特优势： 首先，它对RAS无抑制作用，可以作为最大耐受剂量RAS抑制剂的添加治疗，使得安慰剂可以作为对照设计，简化了临床试验过程。 其次，阿曲生坦还可以与其他药物联合使用，发挥协同作用。如在一种具有肾脏保护作用的药物组合物中，阿曲生坦与依那普利、叶酸类物质联合使用，适用于慢性肾脏疾病或糖尿病肾病，可显著改善患者肾功能。阿曲生坦为高选择性内皮素抑制剂，能逆转或阻断ET-1对于细胞增殖、血管生成、骨质重塑的促进作用及其对血流动力学的影响，减少糖尿病肾病和慢性肾病患者的蛋白尿水平。依那普利为血管紧张素转换酶抑制剂，与叶酸合用可有效保护肾脏，还可降低心脑血管疾病发生风险，三者联用可协同改善肾脏功能，对高血压患者还有降压作用。 03 阿曲生坦临床数据 阿曲生坦治疗IgA肾病患者的III期ALIGN研究的预定中期分析结果令人瞩目。与接受支持治疗（最大耐受剂量和稳定剂量的肾素-血管紧张素系统[RAS]抑制剂）的患者相比，接受阿曲生坦治疗的患者在36周时蛋白尿（以24小时尿蛋白与肌酐比率 [UPCR]衡量）减少了36.1%（p＜0.0001）。这一成果为IgA肾病患者带来了新的希望。 研究还显示，阿曲生坦具有良好的安全性，与前期报道的数据一致。临床前模型表明阿曲生坦可以减少IgAN中的炎症和纤维化，进一步证实了其在治疗IgA肾病中的潜力。 多项研究表明，阿曲生坦在长达一年的时间里持续有效安全地降低IgA肾病患者尿蛋白水平。例如，在II期AFFINITY研究1年的数据结果中，纳入了20例接受最大耐受剂量RASi≥12周、eGFR≥30 mL/min/1.73 m²，0.5 g/g≤UPCR＜1.0 g/g（首次晨尿）的IgA肾病患者。患者每天口服0.75mg阿曲生坦，治疗52周。结果显示，第6 周时24h UPCR显著降低38.2%，第12周降低48.4%，第52周降低45.4%。阿曲生坦耐受性良好，未见治疗相关的严重不良事件或死亡，未见显著的液体潴留。 此外，III期ALIGN研究也评估了阿曲生坦在接受优化支持治疗的成人IgA肾病患者中的疗效和安全性。中期分期数据显示，第36周时，阿曲生坦组24h-UPCR较基线降低了38.1%，安慰剂组较基线降低3.1%，阿曲生坦组24h-UPCR较安慰剂组显著降低达36.1%。阿曲生坦安全性良好，整体安全性和安慰剂相当，提示IgA肾病这一患者群体使用阿曲生坦治疗具有较高安全性，存在较低的液体潴留风险。 在所有亚组分析中，无论性别、年龄、种族、民族或地区，基线蛋白尿水平、估算肾小球滤过率（eGFR）、血压和利尿剂使用情况如何，阿曲生坦治疗IgA肾病患者的蛋白尿获益均一致。研究表明，阿曲生坦耐受性良好、安全性高，有望成为IgA肾病基础治疗中的坚实一环。 04 阿曲生坦的市场价值 随着阿曲生坦的上市，其在肾病药物市场中的价值和份额将成为关注的焦点。据市场研究数据显示，全球肾病药物市场规模持续增长，预计到2026年将达到数十亿美元，年复合增长率保持较高水平。 IgA肾病是全球最常见的原发性肾小球肾炎之一，全球及中国的患者数量众多，且目前存在大量未满足的临床需求。根据相关数据统计，预计到2025年，全球IgA肾病治疗药物市场将从2020年的5.67亿美元增长至11.96亿美元，年复合增长率（CAGR）高达16.1%。而中国市场在这一领域也展现出强劲的增长势头，预计将从2020年的0.37亿美元增加到2025年的1.09亿美元，年复合增长率达到24.6%。 国内肾病用药市场规模庞大，其中，一些传统的肾病药物如糖皮质激素、免疫抑制剂、利尿剂、降压药等仍占据较大市场份额，这些药物经过长期临床应用，医生和患者对其疗效和安全性较为熟悉，因此该市场目前还是以传统药物为主导。 然而，随着新型治疗药物的涌现，如免疫抑制剂、生物制剂等，传统药物的市场份额正逐渐受到挑战。在这一市场中，阿曲生坦具有良好的临床效果和市场需求，因此若阿曲生坦上市并得到广泛应用，预计其销售峰值将较为可观。 结 语 阿曲生坦的上市标志着IgAN治疗领域迎来了重要进展。其独特的作用机制、显著的疗效和良好的安全性，为IgAN患者带来了新的希望。随着其在临床上的广泛应用和更多研究的深入，阿曲生坦有望成为肾病治疗领域的重要药物之一。同时，其市场价值和份额也将随着其在临床上的成功而不断提升。 参考文献： 1. 诺华官网 2. 中国国家药监局药品审评中心官网 *声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！ 全球首个！针对肺癌脑转移的EGFR-TKI新药「佐利替尼」获批上市 首款！默沙东抗肿瘤新药HIF-2α抑制剂国内获批上市 《中国药典》或添新星——利妥昔单抗：B细胞终结者，精准抗癌战士

FILSPARI® (sparsentan) received full FDA approval as the only non-immunosuppressive treatment that significantly slows kidney function decline in IgAN Type C meeting scheduled with FDA to discuss potential sNDA submission for FILSPARI in FSGS sNDA requesting modification of liver monitoring for FILSPARI submitted to FDA Net product sales of FILSPARI totaled $35.6 million for the third quarter of 2024; 505 new PSFs received in the period Total revenue for the third quarter of 2024 was $62.9 million, including net product sales of $61.0 million SAN DIEGO, Oct. 31, 2024 (GLOBE NEWSWIRE) -- Travere Therapeutics, Inc., (NASDAQ: TVTX) today reported its third quarter 2024 financial results and provided a corporate update. “Our performance in the third quarter was exceptional. FILSPARI received full approval as the only medicine that can provide superior preservation of kidney function and replace current standard of care in IgAN, and our commercial team delivered strong growth in sales of FILSPARI in the U.S. Additionally, I am pleased to report that in the weeks since full approval we have seen a meaningful increase in demand, supporting our expectation that the broader label granted upon full approval coupled with the recent draft KDIGO guidelines will strengthen FILSPARI’s growth,” said Eric Dube, Ph.D., president and chief executive officer of Travere Therapeutics. “As we look ahead, we are very well-positioned to further accelerate our growth with FILSPARI. At ASN Kidney Week, we illustrated the potential benefits of using FILSPARI as a first-line treatment, and presented data in combination with other therapies. Our European partner CSL Vifor has launched FILSPARI commercially in the first EU countries. And following the recent PARASOL group recommendation of a proteinuria-based clinical trial endpoint for FSGS, we have scheduled a meeting with the FDA to discuss a potential path forward for FILSPARI in FSGS.” Financial Results for Continuing Operations for the Quarter Ended September 30, 2024 The following financial results discussion compares Travere’s continuing operations. All periods unless otherwise specified have been adjusted to exclude discontinued operations related to the divestiture of the bile acid product portfolio completed on August 31, 2023. Net product sales for the third quarter of 2024 were $61.0 million, compared to $33.9 million for the same period in 2023. The increase is attributable to sales from the ongoing commercial launch of FILSPARI. Research and development (R&D) expenses for the third quarter of 2024 were $51.7 million, compared to $60.6 million for the same period in 2023. For the nine months ended September 30, 2024, R&D expenses were $155.4 million, compared to $185.2 million for the same period in 2023. The decrease is largely attributable to previously announced restructuring initiatives and a decline in costs associated with the development of sparsentan as the Phase 3 programs advance towards completion. On a non-GAAP adjusted basis, R&D expenses were $48.4 million for the third quarter of 2024, compared to $53.8 million for the same period in 2023. Selling, general, and administrative (SG&A) expenses for the third quarter of 2024 were $65.6 million, compared to $67.8 million for the same period in 2023. For the nine months ended September 30, 2024, SG&A expenses were $194.6 million, compared to $202.0 million for the same period in 2023. The decrease is primarily driven by the previously announced restructuring and other cost saving initiatives. On a non-GAAP adjusted basis, SG&A expenses were $49.7 million for the third quarter of 2024, compared to $51.8 million for the same period in 2023. Total other income, net, for the third quarter of 2024 was $1.3 million, compared to total other income, net, of $3.4 million for the same period in 2023. The difference is largely attributable to a decrease in interest income during the period. Net loss including discontinued operations for the third quarter of 2024 was $54.8 million, or $0.70 per basic share, compared to a net income of $150.7 million, or $1.97 per basic share for the same period in 2023. For the nine months ended September 30, 2024, net loss including discontinued operations was $261.3 million, compared to $21.2 million for the same period in 2023. On a non-GAAP adjusted basis, net loss including discontinued operations for the third quarter of 2024 was $35.6 million, or $0.46 per basic share, compared to a net income of $173.5 million, or $2.27 per basic share for the same period in 2023. As of September 30, 2024, the Company had cash, cash equivalents, and marketable securities of $277.4 million. Program Updates FILSPARI® (sparsentan) – IgA Nephropathy (IgAN) On September 5, 2024, the U.S. Food and Drug Administration (FDA) granted full approval to FILSPARI to slow kidney function decline in adults with primary IgAN who are at risk of disease progression. The expanded indication made FILSPARI available to patients with IgAN at risk of progression and the updated label includes data showing superior long-term durable benefit on proteinuria and kidney function preservation that accrued over two years when compared to 300 mg of the active comparator irbesartan.Commercial progress in the ongoing launch has resulted in: 505 new patient start forms (PSFs) received in the third quarter of 2024; a total of 2,989 PSFs have been received since launch in February of 2023.Net product sales of $35.6 million for the third quarter; year-to-date FILSPARI net product sales total $82.6 million. The Company has submitted a supplemental New Drug Application (sNDA) requesting a modification to the frequency of liver monitoring for FILSPARI.In connection with full approval and an expanded indication, the FDA granted an additional term of Orphan Drug Exclusivity for FILSPARI in IgAN expiring in September 2031.In August 2024, Kidney Disease Improving Global Outcomes (KDIGO) published its draft guidelines for IgAN, recommending FILSPARI as a foundational kidney-targeted therapy and lowering the targeted proteinuria level for all IgAN patients to under 0.5 g/day or ideally complete remission (under 0.3 g/day).At ASN Kidney Week (October 23 – 27), the Company presented 9 abstracts on FILSPARI in IgAN, including: An analysis from the PROTECT Study examining the clinical benefit of FILSPARI in IgAN regardless of participants’ baseline proteinuria demonstrating that treatment with FILSPARI reduced proteinuria and preserved kidney function in patients with lower ranges of proteinuria (<1.0 g/g); and patient-reported outcomes from PROTECT suggesting that patients receiving FILSPARI had less burden of kidney disease over time and trend toward improved health-related quality of life compared with maximally dosed irbesartan.Data from a pre-specified interim analysis of the SPARTAN Study demonstrating that as a first-line treatment in patients newly diagnosed with IgAN, FILSPARI delivered a rapid and sustained reduction in proteinuria of approximately 70% from baseline over 24 weeks and was generally well tolerated. In addition, nearly 60% of patients achieved complete remission at any point of time during the treatment period. Throughout the 24 weeks, estimated glomerular filtration rate was stable.Interim data from the SPARTACUS Study demonstrating that FILSPARI when added to stable SGLT2 inhibitors was generally well tolerated and at 24 weeks approximately one-third of patients had their proteinuria reduced by at least 50% after the addition of FILSPARI. The Company also presented new combination data from the ongoing PROTECT open label extension, and real-world clinical experience of FILSPARI in IgAN demonstrating FILSPARI induced further proteinuria reduction and showed favorable safety and additive efficacy results when used in combination with SGLT2 inhibitors or steroids. In the third quarter, the Company’s commercial partner CSL Vifor launched FILSPARI in Germany and Austria, and recently received temporary marketing approval in Switzerland. Sparsentan – Focal Segmental Glomerulosclerosis (FSGS) The Company has scheduled a Type C meeting with FDA to discuss a potential regulatory pathway for a sparsentan FSGS indication. The Company expects to provide an update on the FSGS program by its fourth quarter 2024 earnings call.At ASN Kidney Week 2024, the Company presented two abstracts illustrating the potential benefit of sparsentan in patients with FSGS. A late-breaking presentation in patients with genetic FSGS, a small subgroup of patients that are often resistant to treatment, with results that demonstrated a rapid and sustained proteinuria reduction, including some patients who achieved complete remission and long-term kidney health benefits.Patient-reported outcomes from the DUPLEX Study suggesting health-related quality of life with sparsentan was stable over the two-year treatment period. Pegtibatinase (TVT-058) – Classical Homocystinuria (HCU) In September 2024, the Company announced a voluntary pause of enrollment in the Phase 3 HARMONY Study of pegtibatinase to allow for necessary process improvements in manufacturing scale-up to support commercial scale manufacturing as well as full enrollment in the HARMONY Study.Currently enrolled patients will be able to continue uninterrupted on study medication for the duration of the trials they are participating in.The Company expects to further evaluate the necessary commercial process improvements to enable the continuation of the Phase 3 program and anticipates the earliest date to restart enrollment in the Phase 3 HARMONY Study will be in 2026. Conference Call Information Travere Therapeutics will host a conference call and webcast today, October 31, 2024, at 8:30 a.m. ET to discuss company updates as well as third quarter 2024 financial results. To participate in the conference call, dial +1 (888) 394 8218 (U.S.) or +1 (323) 994-2093 (International), confirmation code 1616163 shortly before 8:30 a.m. ET. The webcast can be accessed on the Investor page of Travere’s website at ir.travere.com/events-presentations. Following the live webcast, an archived version of the call will be available for 30 days on the Company’s website. Use of Non-GAAP Financial Measures To supplement Travere’s financial results and guidance presented in accordance with U.S. generally accepted accounting principles (GAAP), the Company uses certain non-GAAP adjusted financial measures in this press release and the accompanying tables. The Company believes that these non-GAAP financial measures are helpful in understanding its past financial performance and potential future results. They are not meant to be considered in isolation or as a substitute for comparable GAAP measures and should be read in conjunction with the consolidated financial statements prepared in accordance with GAAP. Travere’s management regularly uses these supplemental non-GAAP financial measures internally to understand, manage and evaluate its business and make operating decisions. In addition, Travere believes that the use of these non-GAAP measures enhances the ability of investors to compare its results from period to period and allows for greater transparency with respect to key financial metrics the Company uses in making operating decisions. Investors should note that these non-GAAP financial measures are not prepared under any comprehensive set of accounting rules or principles and do not reflect all of the amounts associated with the Company’s results of operations as determined in accordance with GAAP. Investors should also note that these non-GAAP financial measures have no standardized meaning prescribed by GAAP and, therefore, have limits in their usefulness to investors. In addition, from time to time in the future the Company may exclude other items, or cease to exclude items that it has historically excluded, for purposes of its non-GAAP financial measures; because of the non-standardized definitions, the non-GAAP financial measures as used by the Company in this press release and the accompanying tables may be calculated differently from, and therefore may not be directly comparable to, similarly titled measures used by the Company’s competitors and other companies. As used in this press release, (i) the historical non-GAAP net loss measures exclude from GAAP net loss, as applicable, stock-based compensation expense, amortization and depreciation expense, and income tax; (ii) the historical non-GAAP SG&A expense measures exclude from GAAP SG&A expenses, as applicable, stock-based compensation expense, and amortization and depreciation expense; (iii) the historical non-GAAP R&D expense measures exclude from GAAP R&D expenses, as applicable, stock-based compensation expense, and amortization and depreciation expense. About Travere Therapeutics At Travere Therapeutics, we are in rare for life. We are a biopharmaceutical company that comes together every day to help patients, families and caregivers of all backgrounds as they navigate life with a rare disease. On this path, we know the need for treatment options is urgent – that is why our global team works with the rare disease community to identify, develop and deliver life-changing therapies. In pursuit of this mission, we continuously seek to understand the diverse perspectives of rare patients and to courageously forge new paths to make a difference in their lives and provide hope – today and tomorrow. For more information, visit travere.com. FILSPARI® (sparsentan) U.S. Indication FILSPARI (sparsentan) is indicated to slow kidney function decline in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk for disease progression. IMPORTANT SAFETY INFORMATION BOXED WARNING: HEPATOTOXICITY AND EMBRYO-FETAL TOXICITY Because of the risks of hepatotoxicity and birth defects, FILSPARI is available only through a restricted program called the FILSPARI REMS. Under the FILSPARI REMS, prescribers, patients and pharmacies must enroll in the program. Hepatotoxicity Some Endothelin Receptor Antagonists (ERAs) have caused elevations of aminotransferases, hepatotoxicity, and liver failure. In clinical studies, elevations in aminotransferases (ALT or AST) of at least 3-times the Upper Limit of Normal (ULN) have been observed in up to 3.5% of FILSPARI-treated patients, including cases confirmed with rechallenge. Measure transaminases and bilirubin before initiating treatment and monthly for the first 12 months, and then every 3 months during treatment. Interrupt treatment and closely monitor patients who develop aminotransferase elevations more than 3x ULN. FILSPARI should generally be avoided in patients with elevated aminotransferases (>3x ULN) at baseline because monitoring for hepatotoxicity may be more difficult and these patients may be at increased risk for serious hepatotoxicity. Embryo-Fetal Toxicity FILSPARI can cause major birth defects if used by pregnant patients based on animal data. Therefore, pregnancy testing is required before the initiation of treatment, during treatment and one month after discontinuation of treatment with FILSPARI. Patients who can become pregnant must use effective contraception before the initiation of treatment, during treatment, and for one month after discontinuation of treatment with FILSPARI. Contraindications FILSPARI is contraindicated in patients who are pregnant. Do not coadminister FILSPARI with angiotensin receptor blockers (ARBs), ERAs, or aliskiren. Warnings and Precautions Hepatotoxicity: Elevations in ALT or AST of at least 3-fold ULN have been observed in up to 3.5% of FILSPARI-treated patients, including cases confirmed with rechallenge. While no concurrent elevations in bilirubin >2-times ULN or cases of liver failure were observed in FILSPARI-treated patients, some ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. To reduce the risk of potential serious hepatotoxicity, measure serum aminotransferase levels and total bilirubin prior to initiation of treatment and monthly for the first 12 months, then every 3 months during treatment. Advise patients with symptoms suggesting hepatotoxicity (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching) to immediately stop treatment with FILSPARI and seek medical attention. If aminotransferase levels are abnormal at any time during treatment, interrupt FILSPARI and monitor as recommended. Consider re-initiation of FILSPARI only when hepatic enzyme levels and bilirubin return to pretreatment values and only in patients who have not experienced clinical symptoms of hepatotoxicity. Avoid initiation of FILSPARI in patients with elevated aminotransferases (>3x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult and these patients may be at increased risk for serious hepatotoxicity. Embryo-Fetal Toxicity: FILSPARI can cause fetal harm when administered to a pregnant patient and is contraindicated during pregnancy. Advise patients who can become pregnant of the potential risk to a fetus. Obtain a pregnancy test prior to initiation of treatment with FILSPARI, monthly during treatment, and one month after discontinuation of treatment. Advise patients who can become pregnant to use effective contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with FILSPARI.FILSPARI REMS: Due to the risk of hepatotoxicity and embryo-fetal toxicity, FILSPARI is available only through a restricted program called the FILSPARI REMS. Prescribers, patients, and pharmacies must be enrolled in the REMS program and comply with all requirements (www.filsparirems.com).Hypotension: Hypotension has been observed in patients treated with ARBs and ERAs. There was a greater incidence of hypotension-associated adverse events, some serious, including dizziness, in patients treated with FILSPARI compared to irbesartan. In patients at risk for hypotension, consider eliminating or adjusting other antihypertensive medications and maintaining appropriate volume status. If hypotension develops, despite elimination or reduction of other antihypertensive medications, consider a dose reduction or dose interruption of FILSPARI. A transient hypotensive response is not a contraindication to further dosing of FILSPARI, which can be given once blood pressure has stabilized.Acute Kidney Injury: Monitor kidney function periodically. Drugs that inhibit the renin-angiotensin system (RAS) can cause kidney injury. Patients whose kidney function may depend in part on the activity of the RAS (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute kidney injury on FILSPARI. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in kidney function while on FILSPARI.Hyperkalemia: Monitor serum potassium periodically and treat appropriately. Patients with advanced kidney disease, taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics), or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia. Dosage reduction or discontinuation of FILSPARI may be required.Fluid Retention: Fluid retention may occur with ERAs, and has been observed in clinical studies with FILSPARI. FILSPARI has not been evaluated in patients with heart failure. If clinically significant fluid retention develops, evaluate the patient to determine the cause and the potential need to initiate or modify the dose of diuretic treatment then consider modifying the dose of FILSPARI. Most common adverse reactions The most common adverse reactions (≥5%) are hyperkalemia, hypotension (including orthostatic hypotension), peripheral edema, dizziness, anemia, and acute kidney injury. Drug interactions Renin-Angiotensin System (RAS) Inhibitors and ERAs: Do not coadminister FILSPARI with ARBs, ERAs, or aliskiren due to increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure).Strong and Moderate CYP3A Inhibitors: Avoid concomitant use of FILSPARI with strong CYP3A inhibitors. If a strong CYP3A inhibitor cannot be avoided, interrupt FILSPARI treatment. When resuming treatment with FILSPARI, consider dose titration. Monitor blood pressure, serum potassium, edema, and kidney function regularly when used concomitantly with moderate CYP3A inhibitors. Concomitant use with a strong CYP3A inhibitor increases sparsentan exposure which may increase the risk of FILSPARI adverse reactions.Strong CYP3A Inducers: Avoid concomitant use with a strong CYP3A inducer. Concomitant use with a strong CYP3A inducer decreases sparsentan exposure which may reduce FILSPARI efficacy.Antacids and Acid Reducing Agents: Administer FILSPARI 2 hours before or after administration of antacids. Avoid concomitant use of acid reducing agents (histamine H2 receptor antagonist and PPI proton pump inhibitor) with FILSPARI. Sparsentan exhibits pH-dependent solubility. Antacids or acid reducing agents may decrease sparsentan exposure which may reduce FILSPARI efficacy.Non-Steroidal Anti-Inflammatory Agents (NSAIDs), Including Selective Cyclooxygenase-2 (COX-2) Inhibitors: Monitor for signs of worsening renal function with concomitant use with NSAIDs (including selective COX-2 inhibitors). In patients with volume depletion (including those on diuretic therapy) or with impaired kidney function, concomitant use of NSAIDs (including selective COX-2 inhibitors) with drugs that antagonize the angiotensin II receptor may result in deterioration of kidney function, including possible kidney failure.CYP2B6, 2C9, and 2C19 Substrates: Monitor for efficacy of concurrently administered CYP2B6, 2C9, and 2C19 substrates and consider dosage adjustment in accordance with the Prescribing Information. Sparsentan decreases exposure of these substrates, which may reduce efficacy related to these substrates.P-gp and BCRP Substrates: Avoid concomitant use of sensitive substrates of P-gp and BCRP with FILSPARI. Sparsentan may increase exposure of these transporter substrates, which may increase the risk of adverse reactions related to these substrates.Agents Increasing Serum Potassium: Monitor serum potassium frequently in patients treated with FILSPARI and other agents that increase serum potassium. Concomitant use of FILSPARI with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that raise serum potassium levels may result in hyperkalemia. Please see the full Prescribing Information, including BOXED WARNING, for additional Important Safety Information. Forward-Looking Statements This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, these statements are often identified by the words “on-track,” “positioned,” “look forward to,” “will,” “would,” “may,” “might,” “believes,” “anticipates,” “plans,” “expects,” “intends,” “potential,” or similar expressions. In addition, expressions of strategies, intentions or plans are also forward-looking statements. Such forward-looking statements include, but are not limited to, references to: statements regarding the potential for FILSPARI to replace current standard of care in IgAN and the potential to further accelerate growth with FILSPARI; statements relating to clinical studies, including but not limited to trial design, results and timing related thereto; statements regarding the continuing commercial launch of FILSPARI and trends related thereto; statements regarding the sNDA requesting a modification to the frequency of liver monitoring for FILSPARI and the expected outcome and timing thereof; statements regarding plans to meet with the FDA on a potential sNDA submission for FILSPARI in FSGS and the anticipated timing and outcome thereof; statements and expectations regarding the draft KDIGO guidelines; and statements regarding the voluntary pause of enrollment in the HARMONY Study, including expectations regarding process improvements and the potential timeline to restart enrollment. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among the factors that could cause actual results to differ materially from those indicated in the forward-looking statements are risks related to the timing and outcome of the studies described herein and uncertainties associated with the regulatory review and approval process, as well as risks and uncertainties associated with enrollment of clinical trials for rare diseases, and risks that ongoing or planned clinical trials may not succeed or may be delayed for safety, regulatory or other reasons. The Company also faces risks related to its business and finances in general, the success of its commercial products and risks and uncertainties associated with its preclinical and clinical stage pipeline. Specifically, the Company faces risks associated with the ongoing commercial launch of FILSPARI, market acceptance of its commercial products including efficacy, safety, price, reimbursement, and benefit over competing therapies, risks related to the challenges of manufacturing scale-up, as well as risks associated with the successful development and execution of commercial strategies for such products, including FILSPARI. The risks and uncertainties the Company faces with respect to its preclinical and clinical stage pipeline include risk that the Company’s clinical candidates will not be found to be safe or effective and that current or anticipated future clinical trials will not proceed as planned. There is no guarantee that regulators will grant approval of sparsentan for FSGS. The Company also faces the risk that it will be unable to raise additional funding that may be required to complete development of any or all of its product candidates, including as a result of macroeconomic conditions; risks relating to the Company’s dependence on contractors for clinical drug supply and commercial manufacturing; uncertainties relating to patent protection and exclusivity periods and intellectual property rights of third parties; risks associated with regulatory interactions; and risks and uncertainties relating to competitive products, including current and potential future generic competition with certain of the Company’s products, and technological changes that may limit demand for the Company’s products. The Company also faces additional risks associated with global and macroeconomic conditions, including health epidemics and pandemics, including risks related to potential disruptions to clinical trials, commercialization activity, supply chain, and manufacturing operations. You are cautioned not to place undue reliance on these forward-looking statements as there are important factors that could cause actual results to differ materially from those in forward-looking statements, many of which are beyond our control. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Investors are referred to the full discussion of risks and uncertainties, including under the heading “Risk Factors”, as included in the Company’s most recent Form 10-K, Form 10-Q and other filings with the Securities and Exchange Commission. TRAVERE THERAPEUTICS, INC.CONSOLIDATED BALANCE SHEETS(in thousands, except share amounts) September 30, 2024 December 31, 2023Assets(unaudited) Current assets: Cash and cash equivalents$36,409 $58,176 Marketable debt securities, at fair value 241,030 508,675 Accounts receivable, net 25,170 21,179 Inventory 6,356 9,410 Prepaid expenses and other current assets 15,775 19,335 Total current assets 324,740 616,775 Long-term inventory 36,522 31,494 Property and equipment, net 6,162 7,479 Operating lease right of use assets 15,662 18,061 Intangible assets, net 104,205 104,443 Other assets 17,119 10,661 Total assets$504,410 $788,913 Liabilities and Stockholders' Equity Current liabilities: Accounts payable$23,195 $41,675 Accrued expenses 83,916 118,991 Convertible debt, current portion 68,599 — Deferred revenue, current portion 3,799 7,096 Operating lease liabilities, current portion 5,297 4,909 Other current liabilities 5,232 5,237 Total current liabilities 190,038 177,908 Convertible debt 309,957 377,263 Deferred revenue, less current portion — 1,835 Operating lease liabilities, less current portion 18,581 22,612 Other non-current liabilities 16,288 8,485 Total liabilities 534,864 588,103 Stockholders' Equity: Preferred stock $0.0001 par value; 20,000,000 shares authorized; 0 issued and outstanding as of September 30, 2024 and December 31, 2023 — — Common stock $0.0001 par value; 200,000,000 shares authorized; 77,909,042, and 75,367,117 issued and outstanding as of September 30, 2024 and December 31, 2023, respectively 8 7 Additional paid-in capital 1,357,457 1,327,881 Accumulated deficit (1,386,903) (1,125,622)Accumulated other comprehensive loss (1,016) (1,456)Total stockholders' equity (30,454) 200,810 Total liabilities and stockholders' equity$504,410 $788,913 Note: Certain adjustments / reclassifications have been made to prior periods to conform to current year presentation. TRAVERE THERAPEUTICS, INC.CONSOLIDATED STATEMENTS OF OPERATIONS(in thousands, except share and per share data)(unaudited) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 (unaudited) Net product sales: Tiopronin products$25,382 $25,888 $70,583 $73,112 FILSPARI 35,619 8,044 82,578 14,509 Total net product sales 61,001 33,932 153,161 87,621 License and collaboration revenue 1,897 3,163 5,227 12,558 Total revenue 62,898 37,095 158,388 100,179 Operating expenses: Cost of goods sold 1,626 1,289 5,191 6,886 Research and development 51,679 60,590 155,429 185,244 Selling, general and administrative 65,619 67,801 194,618 201,954 In-process research and development — — 65,205 — Restructuring 123 — 1,035 — Total operating expenses 119,047 129,680 421,478 394,084 Operating loss (56,149) (92,585) (263,090) (293,905) Other income, net: Interest income 3,570 5,842 14,022 14,616 Interest expense (2,777) (2,821) (8,365) (8,513)Other income (expense), net 520 335 (2,737) 220 Total other income, net 1,313 3,356 2,920 6,323 Loss from continuing operations before income tax provision (54,836) (89,229) (260,170) (287,582)Income tax benefit (provision) on continuing operations 84 (12) (192) (155) Loss from continuing operations, net of tax (54,752) (89,241) (260,362) (287,737)(Loss) income from discontinued operations, net of tax (59) 239,976 (919) 266,511 Net (loss) income$(54,811) $150,735 $(261,281) $(21,226) Per share data: Net (loss) income per common share$(0.70) $1.97 $(3.37) $(0.29)Weighted average common shares outstanding 77,779,379 76,305,603 77,473,161 73,523,620 Note: Certain adjustments / reclassifications have been made to prior periods to conform to current year presentation. TRAVERE THERAPEUTICS, INC.RECONCILIATION OF GAAP REPORTED TO NON-GAAP ADJUSTED INFORMATION(in thousands, except share and per share data)(unaudited) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 GAAP operating loss$(56,149) $(92,585) $(263,090) $(293,905) R&D operating expense (51,679) (60,590) (155,429) (185,244) Stock compensation 3,321 4,372 10,752 13,372 Amortization & depreciation — 2,447 — 7,261 Subtotal non-GAAP items 3,321 6,819 10,752 20,633 Non-GAAP R&D expense (48,358) (53,771) (144,677) (164,611) SG&A operating expense (65,619) (67,801) (194,618) (201,954) Stock compensation 4,700 6,949 16,946 22,730 Amortization & depreciation 11,242 9,032 31,462 21,785 Subtotal non-GAAP items 15,942 15,981 48,408 44,515 Non-GAAP SG&A expense (49,677) (51,820) (146,210) (157,439) Subtotal non-GAAP items 19,263 22,800 59,160 65,148 Non-GAAP operating loss$(36,886) $(69,785) $(203,930) $(228,757) GAAP net (loss) income$(54,811) $150,735 $(261,281) $(21,226)Non-GAAP operating loss adjustments 19,263 22,800 59,160 65,148 Income tax benefit (provision) (84) 12 192 155 Non-GAAP net (loss) income (1)$(35,632) $173,547 $(201,929) $44,077 Per share data: Net (loss) income per common share$(0.46) $2.27 $(2.61) $0.60 Weighted average common shares outstanding 77,779,379 76,305,603 77,473,161 73,523,620 (1) Non-GAAP net income (loss) includes income from discontinued operations but excludes non-GAAP adjustments for the effect of discontinued operations. Note: Certain adjustments / reclassifications have been made to prior periods to conform to current year presentation. Contact: Investors:888-969-7879ir@travere.comMedia:888-969-7879mediarelations@travere.com